Submissions for variant NM_000388.4(CASR):c.379G>A (p.Glu127Lys)

dbSNP: rs2074565202

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001586094	SCV001810797	pathogenic	not provided	2019-08-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Lienhardt et al., 2001); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11701698)
Fulgent Genetics, Fulgent Genetics	RCV002480873	SCV002789523	likely pathogenic	Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1	2022-05-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003365296	SCV004061875	likely pathogenic	Nephrolithiasis/nephrocalcinosis	2023-08-04	criteria provided, single submitter	clinical testing	The c.379G>A (p.E127K) alteration is located in exon 3 (coding exon 2) of the CASR gene. This alteration results from a G to A substitution at nucleotide position 379, causing the glutamic acid (E) at amino acid position 127 to be replaced by a lysine (K). Based on the available evidence, the CASR c.379G>A (p.E127K) alteration is classified as likely pathogenic for autosomal dominant CASR-related hypocalcemia; however, it is unlikely to be causative of autosomal recessive neonatal hyperparathyroidism and autosomal dominant hypocalciuric hypercalcemia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as de novo in two individuals with features consistent with CASR-related hypocalcemia (Lienhardt, 2001; Hawkes, 2020). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies showed that the mutant receptor has increased sensitivity to extracellular calcium (Lienhardt, 2001; Quinn, 2004). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV001255709	SCV004175406	likely pathogenic	Autosomal dominant hypocalcemia 1	2023-06-21	criteria provided, single submitter	clinical testing	The CASR c.379G>A variant is classified as Likely Pathogenic (PM2, PS4_Moderate, PM6, PS3_Supporting, PP3) The CASR c.379G>A variant is a single nucleotide change in exon 3/7 of the CASR gene, which is predicted to change the amino acid glutamic acid at position 127 in the protein to lysine. This variant is absent from population databases (PM2). This variant has been identified as a de novo variant in two unrelated affected individuals presenting with phenotypes including hypocalcaemia, seizure and hypoparathyroidism (PS4_moderate, PM6). Functional studies by Lienhardt et al 2001 (PMID: 11701698) demonstrate a gain of function effect for the variant (PS3_Supporting). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in the HGMD database as disease causing (CM013356) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 977805). It has not been reported in dbSNP.
Center for Bone Health, The Children's Hospital of Philadelphia	RCV001255709	SCV001429690	pathogenic	Autosomal dominant hypocalcemia 1		no assertion criteria provided	clinical testing